Cabozantinib: Multi-kinase Inhibitor of MET, AXL, RET, and VEGFR2

Abstract

Cabozantinib is a receptor tyrosine kinase inhibitor (TKI) with activity against a broad range of targets, including MET, RET, AXL, VEGFR2, FLT3, and c-KIT. Activity of cabozantinib towards a broad range of tumor models could be detected in several preclinical studies. Of note, cabozantinib decreases metastasis potential and tumor invasiveness when compared with placebo or agents that target VEGFR and have no activity against MET. Cabozantinib is clinically approved for the treatment of medullary thyroid cancer (MTC) and for renal cell cancer (RCC) in the second line. In MTC gain of function mutations, mutations of RET are central for tumorigenesis. Hereditary forms of MTC (MEN II) are caused by germline mutations of RET, in sporadic MTC up to 50% of cases RET mutations occur. Both MET and AXL have been described as mechanisms facilitating resistance against VEGFR-targeted tyrosine kinase therapy in clear cell RCC. Accordingly, cabozantinib has shown activity in RCC patients progressing after first-line VEGFR-TKI therapy in the pivotal METEOR trial. This phase III trial reported a benefit of 4.9 months in survival and an increase in response rate compared to standard everolimus over all patient subgroups. Of particular interest are the effects on patients with bone metastasis, which have a worse prognosis. In these patients, the beneficial effects of cabozantinib over everolimus were even more pronounced. Side effects of interest include diarrhea, hypertension, fatigue, and hand–foot syndrome.